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De Novo PITX1 Expression Controls Bi-Stable Transcriptional Circuits to Govern Self-Renewal and Differentiation in Squamous Cell Carcinoma

Sastre-Perona, Ana; Hoang-Phou, Steven; Leitner, Marie-Christin; Okuniewska, Martyna; Meehan, Shane; Schober, Markus
Basal tumor propagating cells (TPCs) control squamous cell carcinoma (SCC) growth by self-renewing and differentiating into supra-basal SCC cells, which lack proliferative potential. While transcription factors such as SOX2 and KLF4 can drive these behaviors, their molecular roles and regulatory interactions with each other have remained elusive. Here, we show that PITX1 is specifically expressed in TPCs, where it co-localizes with SOX2 and TRP63 and determines cell fate in mouse and human SCC. Combining gene targeting with chromatin immunoprecipitation sequencing (ChIP-seq) and transcriptomic analyses reveals that PITX1 cooperates with SOX2 and TRP63 to sustain an SCC-specific transcriptional feed-forward circuit that maintains TPC-renewal, while inhibiting KLF4 expression and preventing KLF4-dependent differentiation. Conversely, KLF4 represses PITX1, SOX2, and TRP63 expression to prevent TPC expansion. This bi-stable, multi-input network reveals a molecular framework that explains self-renewal, aberrant differentiation, and SCC growth in mice and humans, providing clues for developing differentiation-inducing therapeutic strategies.
PMID: 30713093
ISSN: 1875-9777
CID: 3631872

SOX2 is a cancer-specific regulator of tumour initiating potential in cutaneous squamous cell carcinoma

Siegle, Jasmin M; Basin, Alice; Sastre-Perona, Ana; Yonekubo, Yoshiya; Brown, Jessie; Sennett, Rachel; Rendl, Michael; Tsirigos, Aristotelis; Carucci, John A; Schober, Markus
Although the principles that balance stem cell self-renewal and differentiation in normal tissue homeostasis are beginning to emerge, it is still unclear whether cancer cells with tumour initiating potential are similarly governed, or whether they have acquired distinct mechanisms to sustain self-renewal and long-term tumour growth. Here we show that the transcription factor Sox2, which is not expressed in normal skin epithelium and is dispensable for epidermal homeostasis, marks tumour initiating cells (TICs) in cutaneous squamous cell carcinomas (SCCs). We demonstrate that Sox2 is required for SCC growth in mouse and human, where it enhances Nrp1/Vegf signalling to promote the expansion of TICs along the tumour-stroma interface. Our findings suggest that distinct transcriptional programmes govern self-renewal and long-term growth of TICs and normal skin epithelial stem and progenitor cells. These programmes present promising diagnostic markers and targets for cancer-specific therapies.
PMCID:4207965
PMID: 25077433
ISSN: 2041-1723
CID: 1090252

Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells

Casanova-Acebes, María; Dalla, Erica; Leader, Andrew M; LeBerichel, Jessica; Nikolic, Jovan; Morales, Blanca M; Brown, Markus; Chang, Christie; Troncoso, Leanna; Chen, Steven T; Sastre-Perona, Ana; Park, Matthew D; Tabachnikova, Alexandra; Dhainaut, Maxime; Hamon, Pauline; Maier, Barbara; Sawai, Catherine M; Agulló-Pascual, Esperanza; Schober, Markus; Brown, Brian D; Reizis, Boris; Marron, Thomas; Kenigsberg, Ephraim; Moussion, Christine; Benaroch, Philippe; Aguirre-Ghiso, Julio A; Merad, Miriam
Macrophages have a key role in shaping the tumour microenvironment (TME), tumour immunity and response to immunotherapy, which makes them an important target for cancer treatment1,2. However, modulating macrophages has proved extremely difficult, as we still lack a complete understanding of the molecular and functional diversity of the tumour macrophage compartment. Macrophages arise from two distinct lineages. Tissue-resident macrophages self-renew locally, independent of adult haematopoiesis3-5, whereas short-lived monocyte-derived macrophages arise from adult haematopoietic stem cells, and accumulate mostly in inflamed lesions1. How these macrophage lineages contribute to the TME and cancer progression remains unclear. To explore the diversity of the macrophage compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we performed single-cell RNA sequencing of tumour-associated leukocytes. We identified distinct populations of macrophages that were enriched in human and mouse lung tumours. Using lineage tracing, we discovered that these macrophage populations differ in origin and have a distinct temporal and spatial distribution in the TME. Tissue-resident macrophages accumulate close to tumour cells early during tumour formation to promote epithelial-mesenchymal transition and invasiveness in tumour cells, and they also induce a potent regulatory T cell response that protects tumour cells from adaptive immunity. Depletion of tissue-resident macrophages reduced the numbers and altered the phenotype of regulatory T cells, promoted the accumulation of CD8+ T cells and reduced tumour invasiveness and growth. During tumour growth, tissue-resident macrophages became redistributed at the periphery of the TME, which becomes dominated by monocyte-derived macrophages in both mouse and human NSCLC. This study identifies the contribution of tissue-resident macrophages to early lung cancer and establishes them as a target for the prevention and treatment of early lung cancer lesions.
PMID: 34135508
ISSN: 1476-4687
CID: 4917532

Oncogenic melanocyte stem cells, driven by regenerative niche signals, give rise to heterogeneous melanoma resembling human melanoma [Meeting Abstract]

Sun, Q.; Katehis, I.; Lee, W.; Mohri, Y.; Takeo, M.; Lim, C.; Xu, X.; Myung, P. S.; Atit, R.; Taketo, M.; Moubarak, R.; Schober, M.; Osman, I.; Gay, D.; Saur, D.; Nishimura, E. K.; Ito, M.
ISI:000554564400573
ISSN: 0022-202x
CID: 4560342

A novel mouse model demonstrates that oncogenic melanocyte stem cells engender melanoma resembling human disease

Sun, Qi; Lee, Wendy; Mohri, Yasuaki; Takeo, Makoto; Lim, Chae Ho; Xu, Xiaowei; Myung, Peggy; Atit, Radhika P; Taketo, M Mark; Moubarak, Rana S; Schober, Markus; Osman, Iman; Gay, Denise L; Saur, Dieter; Nishimura, Emi K; Ito, Mayumi
Melanoma, the deadliest skin cancer, remains largely incurable at advanced stages. Currently, there is a lack of animal models that resemble human melanoma initiation and progression. Recent studies using a Tyr-CreER driven mouse model have drawn contradictory conclusions about the potential of melanocyte stem cells (McSCs) to form melanoma. Here, we employ a c-Kit-CreER-driven model that specifically targets McSCs to show that oncogenic McSCs are a bona fide source of melanoma that expand in the niche, and then establish epidermal melanomas that invade into the underlying dermis. Further, normal Wnt and Endothelin niche signals during hair anagen onset are hijacked to promote McSC malignant transformation during melanoma induction. Finally, molecular profiling reveals strong resemblance of murine McSC-derived melanoma to human melanoma in heterogeneity and gene signatures. These findings provide experimental validation of the human melanoma progression model and key insights into the transformation and heterogeneity of McSC-derived melanoma.
PMCID:6828673
PMID: 31685822
ISSN: 2041-1723
CID: 4172362

Self-renewal and differentiation in squamous cell carcinomas

Sastre-Perona, Ana; Hoang-Phou, Steven; Schober, Markus
PMID: 31627191
ISSN: 1945-4589
CID: 4140782

KLF4 as a rheostat of osteolysis and osteogenesis in prostate tumors in the bone

Tassone, Evelyne; Bradaschia-Correa, Vivian; Xiong, Xiaozhong; Sastre-Perona, Ana; Josephson, Anne Marie; Khodadadi-Jamayran, Alireza; Melamed, Jonathan; Bu, Lei; Kahler, David J; Ossowski, Liliana; Leucht, Philipp; Schober, Markus; Wilson, Elaine L
We previously showed that KLF4, a gene highly expressed in murine prostate stem cells, blocks the progression of indolent intraepithelial prostatic lesions into aggressive and rapidly growing tumors. Here, we show that the anti-tumorigenic effect of KLF4 extends to PC3 human prostate cancer cells growing in the bone. We compared KLF4 null cells with cells transduced with a DOX-inducible KLF4 expression system, and find KLF4 function inhibits PC3 growth in monolayer and soft agar cultures. Furthermore, KLF4 null cells proliferate rapidly, forming large, invasive, and osteolytic tumors when injected into mouse femurs, whereas KLF4 re-expression immediately after their intra-femoral inoculation blocks tumor development and preserves a normal bone architecture. KLF4 re-expression in established KLF4 null bone tumors inhibits their osteolytic effects, preventing bone fractures and inducing an osteogenic response with new bone formation. In addition to these profound biological changes, KLF4 also induces a transcriptional shift from an osteolytic program in KLF4 null cells to an osteogenic program. Importantly, bioinformatic analysis shows that genes regulated by KLF4 overlap significantly with those expressed in metastatic prostate cancer patients and in three individual cohorts with bone metastases, strengthening the clinical relevance of the findings in our xenograft model.
PMID: 31239516
ISSN: 1476-5594
CID: 3953842

KLF4, A Gene Regulating Prostate Stem Cell Homeostasis, Is a Barrier to Malignant Progression and Predictor of Good Prognosis in Prostate Cancer

Xiong, Xiaozhong; Schober, Markus; Tassone, Evelyne; Khodadadi-Jamayran, Alireza; Sastre-Perona, Ana; Zhou, Hua; Tsirigos, Aristotelis; Shen, Steven; Chang, Miao; Melamed, Jonathan; Ossowski, Liliana; Wilson, Elaine L
There is a considerable need to identify those individuals with prostate cancer who have indolent disease. We propose that genes that control adult stem cell homeostasis in organs with slow turnover, such as the prostate, control cancer fate. One such gene, KLF4, overexpressed in murine prostate stem cells, regulates their homeostasis, blocks malignant transformation, and controls the self-renewal of tumor-initiating cells. KLF4 loss induces the molecular features of aggressive cancer and converts PIN lesions to invasive sarcomatoid carcinomas; its re-expression in vivo reverses this process. Bioinformatic analysis links these changes to human cancer. KLF4 and its downstream targets make up a gene signature that identifies indolent tumors and predicts recurrence-free survival. This approach may improve prognosis and identify therapeutic targets for advanced cancer.
PMID: 30540935
ISSN: 2211-1247
CID: 3543262

Cellular quiescence: How TGFβ protects cancer cells from chemotherapy

Brown, Jessie A; Schober, Markus
Using a functional proliferation reporter we identified quiescent tumor propagating cancer cells (TPCs) in intact squamous cell carcinomas, and found that TGFβ signaling controls their reversible entry into a growth arrested state, which protects TPCs from chemotherapy. TPCs with compromised TGFβ/Smad signaling can't enter quiescence and subsequently die from chemotherapy.
PMCID:5821413
PMID: 29487897
ISSN: 2372-3556
CID: 2965532

TGF-beta-Induced Quiescence Mediates Chemoresistance of Tumor-Propagating Cells in Squamous Cell Carcinoma

Brown, Jessie A; Yonekubo, Yoshiya; Hanson, Nicole; Sastre-Perona, Ana; Basin, Alice; Rytlewski, Julie A; Dolgalev, Igor; Meehan, Shane; Tsirigos, Aristotelis; Beronja, Slobodan; Schober, Markus
Squamous cell carcinomas (SCCs) are heterogeneous tumors sustained by tumor-propagating cancer cells (TPCs). SCCs frequently resist chemotherapy through still unknown mechanisms. Here, we combine H2B-GFP-based pulse-chasing with cell-surface markers to distinguish quiescent from proliferative TPCs within SCCs. We find that quiescent TPCs resist DNA damage and exhibit increased tumorigenic potential in response to chemotherapy, whereas proliferative TPCs undergo apoptosis. Quiescence is regulated by TGF-beta/SMAD signaling, which directly regulates cell-cycle gene transcription to control a reversible G1 cell-cycle arrest, independent of p21CIP function. Indeed, genetic or pharmacological TGF-beta inhibition increases the susceptibility of TPCs to chemotherapy because it prevents entry into a quiescent state. These findings provide direct evidence that TPCs can reversibly enter a quiescent, chemoresistant state and thereby underscore the need for combinatorial approaches to improve treatment of chemotherapy-resistant SCCs.
PMCID:5778452
PMID: 29100014
ISSN: 1875-9777
CID: 2765752