Impact of context-dependent autophagy states on tumor progression
Assi, Mohamad; Kimmelman, Alec C
Macroautophagy is a cellular quality-control process that degrades proteins, protein aggregates and damaged organelles. Autophagy plays a fundamental role in cancer where, in the presence of stressors (for example, nutrient starvation, hypoxia, mechanical pressure), tumor cells activate it to degrade intracellular substrates and provide energy. Cell-autonomous autophagy in tumor cells and cell-nonautonomous autophagy in the tumor microenvironment and in the host converge on mechanisms that modulate metabolic fitness, DNA integrity and immune escape and, consequently, support tumor growth. In this Review, we will discuss insights into the tumor-modulating roles of autophagy in different contexts and reflect on how future studies using physiological culture systems may help to understand the complexity and open new therapeutic avenues.
Autophagy supports mitochondrial metabolism through the regulation of iron homeostasis in pancreatic cancer
Mukhopadhyay, Subhadip; Encarnación-Rosado, Joel; Lin, Elaine Y; Sohn, Albert S W; Zhang, Huan; Mancias, Joseph D; Kimmelman, Alec C
Pancreatic ductal adenocarcinoma (PDAC) cells maintain a high level of autophagy, allowing them to thrive in an austere microenvironment. However, the processes through which autophagy promotes PDAC growth and survival are still not fully understood. Here, we show that autophagy inhibition in PDAC alters mitochondrial function by losing succinate dehydrogenase complex iron sulfur subunit B expression by limiting the availability of the labile iron pool. PDAC uses autophagy to maintain iron homeostasis, while other tumor types assessed require macropinocytosis, with autophagy being dispensable. We observed that cancer-associated fibroblasts can provide bioavailable iron to PDAC cells, promoting resistance to autophagy ablation. To overcome this cross-talk, we used a low-iron diet and demonstrated that this augmented the response to autophagy inhibition therapy in PDAC-bearing mice. Our work highlights a critical link between autophagy, iron metabolism, and mitochondrial function that may have implications for PDAC progression.
Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer
Tintelnot, Joseph; Xu, Yang; Lesker, Till R; Schönlein, Martin; Konczalla, Leonie; Giannou, Anastasios D; Pelczar, Penelope; Kylies, Dominik; Puelles, Victor G; Bielecka, Agata A; Peschka, Manuela; Cortesi, Filippo; Riecken, Kristoffer; Jung, Maximilian; Amend, Lena; Bröring, Tobias S; Trajkovic-Arsic, Marija; Siveke, Jens T; Renné, Thomas; Zhang, Danmei; Boeck, Stefan; Strowig, Till; Uzunoglu, Faik G; Güngör, Cenap; Stein, Alexander; Izbicki, Jakob R; Bokemeyer, Carsten; Sinn, Marianne; Kimmelman, Alec C; Huber, Samuel; Gagliani, Nicola
Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second most deadly cancer by 2040, owing to the high incidence of metastatic disease and limited responses to treatment1,2. Less than half of all patients respond to the primary treatment for PDAC, chemotherapy3,4, and genetic alterations alone cannot explain this5. Diet is an environmental factor that can influence the response to therapies, but its role in PDAC is unclear. Here, using shotgun metagenomic sequencing and metabolomic screening, we show that the microbiota-derived tryptophan metabolite indole-3-acetic acid (3-IAA) is enriched in patients who respond to treatment. Faecal microbiota transplantation, short-term dietary manipulation of tryptophan and oral 3-IAA administration increase the efficacy of chemotherapy in humanized gnotobiotic mouse models of PDAC. Using a combination of loss- and gain-of-function experiments, we show that the efficacy of 3-IAA and chemotherapy is licensed by neutrophil-derived myeloperoxidase. Myeloperoxidase oxidizes 3-IAA, which in combination with chemotherapy induces a downregulation of the reactive oxygen species (ROS)-degrading enzymes glutathione peroxidase 3 and glutathione peroxidase 7. All of this results in the accumulation of ROS and the downregulation of autophagy in cancer cells, which compromises their metabolic fitness and, ultimately, their proliferation. In humans, we observed a significant correlation between the levels of 3-IAA and the efficacy of therapy in two independent PDAC cohorts. In summary, we identify a microbiota-derived metabolite that has clinical implications in the treatment of PDAC, and provide a motivation for considering nutritional interventions during the treatment of patients with cancer.
Reprogramming of tissue metabolism during cancer metastasis
Ganguly, Koelina; Kimmelman, Alec C.
Cancer is a systemic disease that involves malignant cell-intrinsic and -extrinsic metabolic adaptations. Most studies have tended to focus on elucidating the metabolic vulnerabilities in the primary tumor microenvironment, leaving the metastatic microenvironment less explored. In this opinion article, we discuss the current understanding of the metabolic crosstalk between the cancer cells and the tumor microenvironment, both at local and systemic levels. We explore the possible influence of the primary tumor secretome to metabolically and epigenetically rewire the nonmalignant distant organs during prometastatic niche formation and successful metastatic colonization by the cancer cells. In an attempt to understand the process of prometastatic niche formation, we have speculated how cancer may hijack the inherent regenerative propensity of tissue parenchyma during metastatic colonization.
EXPLORATORY PLATFORM TRIAL TO EVALUATE IMMUNOTHERAPY COMBINATIONS WITH CHEMOTHERAPY FOR THE TREATMENT OF PATIENTS WITH PREVIOUSLY UNTREATED METASTATIC PANCREATIC ADENOCARCINOMA (REVOLUTION) [Meeting Abstract]
Lyman, J; O'Reilly, E; Wainberg, Z; Fisher, G; Wolff, R; Ko, A; O'Hara, M; Singh, H; Amaravadi, R; Kimmelman, A; Collison, E; Khalil, D; Schmidberger, R; Cabanski, C; Maddock, S; Spasic, M; Maurer, D; Da, Silva D; Perry, C; Yu, J X; Padron, L; Bucktrout, S; Butterfield, L; Ibrahim, R; Fairchild, J; LaVallee, T; Lillie, T; Hoos, W; Boffo, S; Dugan, U; O'Donnell-Tormey, J; Vonderheide, R
Background Metastatic pancreatic adenocarcinoma (mPDAC) remains notoriously treatment-refractory, particularly to immunotherapy; however, recent promise has been demonstrated with chemoimmunotherapy combinations.1,2 REVOLUTION is an adaptive platform trial, designed to further these advancements by assessing the safety and antitumor activity of parallel, novel chemoimmunotherapy combinations in patients with untreated mPDAC. Coupled with deep immune biomarker profiling, this approach will enable rapid insights from each combination, generating data to be leveraged for future cohorts. REVOLUTION also builds upon the collaborative framework between academic, nonprofit and industry partners, laid by the PRINCE trial.1 Methods REVOLUTION is an open-label, non-randomized, exploratory platform trial. Each cohort utilizes a Simon twostage design: Stage 1 enrolling n=15 patients, expansion to Stage 2 (an additional n=15 patients) based on the totality of safety, efficacy and biomarker analyses. Key inclusion criteria histologically or cytologically confirmed, treatment-naive, recurrent or de novo mPDAC, measurable by RECIST 1.1. Primary endpoints: safety, as assessed by the incidence and severity of adverse events. Secondary endpoints: ORR (per RECIST 1.1), DCR, DOR, PFS, and OS. Exploratory endpoints: pharmacodynamics and association of tumor, blood, and stool biomarkers with clinical activity. Three cohorts are underway, all using a backbone of standard- of-care gemcitabine/nab-paclitaxel (gem/nP). Cohort A: nivolumab + ipilimumab + gem/nP. We hypothesize chemotherapy will induce antigen release, ipilimumab will enhance T cell activation, proliferation and tumor infiltration, and nivolumab will overcome immunosuppression while re-invigorating therapeutically relevant T cells. Cohort B: high-dose hydroxychloroquine (HCQ), an autophagy inhibitor, + ipilimumab + gem/nP. The same mechanisms of action for chemotherapy and ipilimumab as Cohort A are hypothesized, with HCQ augmenting T cell priming and cytotoxicity by upregulating MHC-1.3 Cohort C: NG-350A, an intravenously administered adenovirus that selectively replicates in tumor cells and expresses a fully human agonistic CD40 monoclonal antibody, + ipilimumab + gem/nP. The same mechanisms of action for chemotherapy and ipilimumab as Cohorts A and B are hypothesized, with NG-350A re-programming the tumor microenvironment, activating antigen-presenting cells, and facilitating immune priming.4 In accordance with recent findings, all current cohorts are also testing a novel dosing schedule of ipilimumab (2 doses at 1 mg/kg, Q6W).5 Results Cohorts A and B are fully enrolled for Stage 1 and accumulating data to support an expansion decision. Cohort C is in development
Precision medicine in pancreatic cancer: Patient derived organoid pharmacotyping is a predictive biomarker of clinical treatment response
SeppÃ¤lÃ¤, Toni T; Zimmerman, Jacquelyn W; Suri, Reecha; Zlomke, Haley; Ivey, Gabriel D; Szabolcs, Annamaria; Shubert, Christopher R; Cameron, John L; Burns, William R; Lafaro, Kelly J; He, Jin; Wolfgang, Christopher L; Zou, Ying S; Zheng, Lei; Tuveson, David A; Eshlemann, James R; Ryan, David P; Kimmelman, Alec C; Hong, Theodore S; Ting, David T; Jaffee, Elizabeth M; Burkhart, Richard A
RATIONALE/BACKGROUND:Patient-derived organoids (PDOs) are a promising technology to support precision medicine initiatives for patients with pancreatic ductal adenocarcinoma (PDAC). PDOs may improve clinical next-generation sequencing (NGS) and enable rapid ex vivo chemotherapeutic screening (pharmacotyping). METHODS:PDOs were derived from tissues obtained during surgical resection and endoscopic biopsies and studied with NGS and pharmacotyping. PDO-specific pharmacotype is assessed prospectively as a predictive biomarker of clinical therapeutic response by leveraging data from a randomized-controlled clinical trial. RESULTS:Clinical sequencing pipelines often fail to detect PDAC-associated somatic mutations in surgical specimens that demonstrate a good pathological response to previously administered chemotherapy. Sequencing the PDOs derived from these surgical specimens, after biomass expansion, improves the detection of somatic mutations and enables quantification of copy number variants. The detection of clinically relevant mutations and structural variants is improved following PDO biomass expansion. On clinical trial, PDOs were derived from biopsies of treatment naÃ¯ve patients prior to treatment with FOLFIRINOX (FFX). Ex vivo PDO pharmacotyping with FFX components predicted clinical therapeutic response in these patients with borderline resectable or locally advanced PDAC treated in a neoadjuvant or induction paradigm. PDO pharmacotypes suggesting sensitivity to FFX components were associated with longitudinal declines of tumor marker, CA-19-9 and favorable RECIST imaging response. CONCLUSION/CONCLUSIONS:PDOs establishment from tissues obtained from patients previously receiving cytotoxic chemotherapies can be accomplished in a clinically-certified laboratory. Sequencing PDOs following biomass expansion improves clinical sequencing quality. High in-vitro sensitivity to standard-of-care chemotherapeutics predicts good clinical response to systemic chemotherapy in PDAC.
Supportive Oncology Care at Home Intervention for Patients With Pancreatic Cancer
Nipp, Ryan D; Gaufberg, Eva; Vyas, Charu; Azoba, Chinenye; Qian, Carolyn L; Jaggers, Jordon; Weekes, Colin D; Allen, Jill N; Roeland, Eric J; Parikh, Aparna R; Miller, Laurie; Wo, Jennifer Y; Smith, Melissa Hennessey; Brown, Patricia M C; Shulman, Eliza; Fernandez-Del Castillo, Carlos; Kimmelman, Alec C; Ting, David; Hong, Theodore S; Greer, Joseph A; Ryan, David P; Temel, Jennifer S; El-Jawahri, Areej
PURPOSE/UNASSIGNED:We sought to determine the feasibility of delivering a Supportive Oncology Care at Home intervention among patients with pancreatic cancer. METHODS/UNASSIGNED:We prospectively enrolled patients with pancreatic cancer from a parent trial of neoadjuvant fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX). The intervention entailed (1) remote monitoring of patient-reported symptoms, vital signs, and body weight; (2) a hospital-at-home care model; and (3) structured communication with the oncology team. We defined the intervention as feasible if â‰¥ 60% of patients enrolled in the study and â‰¥ 60% completed the daily assessments within the first 2-weeks of enrollment. We determined rates of treatment delays, urgent clinic visits, emergency department visits, and hospitalizations among those who did (n = 20) and did not (n = 24) receive Supportive Oncology Care at Home from the parent trial. RESULTS/UNASSIGNED:62.5%) compared with those not receiving the intervention from the same parent trial. CONCLUSION/UNASSIGNED:Findings demonstrate the feasibility and acceptability of a Supportive Oncology Care at Home intervention. Future work will investigate the efficacy of this intervention for decreasing health care use and improving patient outcomes.
Metabolic reprogramming of tumor-associated macrophages by collagen turnover promotes fibrosis in pancreatic cancer
LaRue, Madeleine M; Parker, Seth; Puccini, Joseph; Cammer, Michael; Kimmelman, Alec C; Bar-Sagi, Dafna
SignificanceThe highly desmoplastic and immunosuppressive microenvironment of pancreatic tumors is a major determinant of the aggressive nature and therapeutic resistance of pancreatic cancer. Therefore, improving our understanding of the mechanisms that regulate the composition and function of the pancreatic tumor microenvironment is critical for the design of intervention strategies for this devastating malignancy. This study identifies a modality for the reprogramming of tumor-associated macrophages involving collagen scavenging followed by a metabolic switch toward a profibrotic paracrine phenotype. These findings establish a molecular framework for the elucidation of regulatory processes that could be harnessed to mitigate the stroma-dependent protumorigenic effects in pancreatic cancer.
USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer
Hou, Pingping; Ma, Xingdi; Yang, Zecheng; Zhang, Qiang; Wu, Chang-Jiun; Li, Jun; Tan, Lin; Yao, Wantong; Yan, Liang; Zhou, Xin; Kimmelman, Alec C; Lorenzi, Philip L; Zhang, Jianhua; Jiang, Shan; Spring, Denise; Wang, Y Alan; DePinho, Ronald A
Activating mutations in KRAS (KRAS*) are present in nearly all pancreatic ductal adenocarcinoma (PDAC) cases and critical for tumor maintenance. By using an inducible KRAS* PDAC mouse model, we identified a deubiquitinase USP21-driven resistance mechanism to anti-KRAS* therapy. USP21 promotes KRAS*-independent tumor growth via its regulation of MARK3-induced macropinocytosis, which serves to maintain intracellular amino acid levels for anabolic growth. The USP21-mediated KRAS* bypass, coupled with the frequent amplification of USP21 in human PDAC tumors, encourages the assessment of USP21 as a novel drug target as well as a potential parameter that may affect responsiveness to emergent anti-KRAS* therapy.
The polar oxy-metabolome reveals the 4-hydroxymandelate CoQ10 synthesis pathway
Banh, Robert S; Kim, Esther S; Spillier, Quentin; Biancur, Douglas E; Yamamoto, Keisuke; Sohn, Albert S W; Shi, Guangbin; Jones, Drew R; Kimmelman, Alec C; Pacold, Michael E
Oxygen is critical for a multitude of metabolic processes that are essential for human life. Biological processes can be identified by treating cells with 18O2 or other isotopically labelled gases and systematically identifying biomolecules incorporating labeled atoms. Here we labelled cell lines of distinct tissue origins with 18O2 to identify the polar oxy-metabolome, defined as polar metabolitesÂ labelled with 18O under different physiological O2 tensions. The most highly 18O-labelled feature was 4-hydroxymandelate (4-HMA).Â We demonstrate that 4-HMA is produced by hydroxyphenylpyruvate dioxygenase-like (HPDL), a protein of previously unknown function in human cells. We identify 4-HMA as an intermediate involved in the biosynthesis of the coenzyme Q10 (CoQ10) headgroup in human cells. The connection of HPDL to CoQ10 biosynthesis provides crucial insights into the mechanisms underlying recently described neurological diseases related to HPDL deficiencies1-4 and cancers with HPDL overexpression5.