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Metastatic colorectal cancer cells maintain the TGF? program and use TGFBI to fuel angiogenesis.

ABSTRACT: Colorectal cancer (CRC) cells are traditionally considered unresponsive to TGF? due to mutations in the receptors and/or downstream signaling molecules. TGF? influences CRC cells only indirectly via stromal cells, such as cancer-associated fibroblasts. However, CRC cell ability to directly respond to TGF? currently remains unexplored. This represents a missed opportunity for diagnostic and therapeutic interventions. Methods: We examined whether cancer cells from primary CRC and liver metastases respond to TGF? by inducing TGF?-induced protein ig-h3 (TGFBI) expression, and the contribution of canonical and non-canonical TGF? signaling pathways to this effect. We then investigated in vitro and in vivo TGFBI impact on metastasis formation and angiogenesis. Using patient serum samples and an orthotopic mouse model of CRC liver metastases we assessed the diagnostic/tumor targeting value of novel antibodies against TGFBI. Results: Metastatic CRC cells, such as circulating tumor cells, directly respond to TGF?. These cells were characterized by the absence of TGF? receptor mutations and the frequent presence of p53 mutations. The pro-tumorigenic program orchestrated by TGF? in CRC cells was mediated through TGFBI, the expression of which was positively regulated by non-canonical TGF? signaling cascades. TGFBI inhibition was sufficient to significantly reduce liver metastasis formation in vivo. Moreover, TGFBI pro-tumorigenic function was linked to its ability to stimulate angiogenesis. TGFBI levels were higher in serum samples from untreated patients with CRC than in patients who were receiving chemotherapy. A radiolabeled anti-TGFBI antibody selectively targeted metastatic lesions in vivo, underscoring its diagnostic and therapeutic potential. Conclusions: TGF? signaling in CRC cells directly contributes to their metastatic potential and stromal cell-independence. Proteins downstream of activated TGF?, such as TGFBI, represent novel diagnostic and therapeutic targets for more specific anti-metastatic therapies.

SUBMITTER: Chiavarina B

PROVIDER: S-EPMC7778592 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Metastatic colorectal cancer cells maintain the TGFβ program and use TGFBI to fuel angiogenesis.

Chiavarina Barbara B Costanza Brunella B Ronca Roberto R Blomme Arnaud A Rezzola Sara S Chiodelli Paola P Giguelay Ambre A Belthier Guillame G Doumont Gilles G Van Simaeys Gaetan G Lacroix Simon S Yokobori Takehiko T Erkhem-Ochir Bilguun B Balaguer Patrick P Cavailles Vincent V Fabbrizio Eric E Di Valentin Emmanuel E Gofflot Stephanie S Detry Olivier O Jerusalem Guy G Goldman Serge S Delvenne Philippe P Bellahcène Akeila A Pannequin Julie J Castronovo Vincent V Turtoi Andrei A

Theranostics 20210101 4

Colorectal cancer (CRC) cells are traditionally considered unresponsive to TGFβ due to mutations in the receptors and/or downstream signaling molecules. TGFβ influences CRC cells only indirectly via stromal cells, such as cancer-associated fibroblasts. However, CRC cell ability to directly respond to TGFβ currently remains unexplored. This represents a missed opportunity for diagnostic and therapeutic interventions. <b>Methods:</b> We examined whether cancer cells from primary CRC and liver meta ...[more]

PMID: 33408771

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Project description:IntroductionBreast tumors are comprised of distinct cancer cell populations which differ in their tumorigenic and metastatic capacity. Characterization of cell surface markers enables investigators to distinguish between cancer stem cells and their counterparts. CD24 is a well-known cell surface marker for mammary epithelial cells isolation, recently it was suggested as a potential prognostic marker in a wide variety of malignancies. Here, we demonstrate that CD24(+) cells create intra-tumor heterogeneity, and display highly metastatic properties.MethodsThe mammary carcinoma Mvt1 cells were sorted into CD24(-) and CD24(+) cells. Both subsets were morphologically and phenotypically characterized, and tumorigenic capacity was assessed via orthotopic inoculation of each subset into the mammary fat pad of wild-type and MKR mice. The metastatic capacity of each subset was determined with the tail vein metastasis assay. The role of CD24 in tumorigenesis was further examined with shRNA technology. GFP-labeled cells were monitored in vivo for differentiation. The genetic profile of each subset was analyzed using RNA sequencing.ResultsCD24(+) cells displayed a more spindle-like cytoplasm. The cells formed mammospheres in high efficiency and CD24(+) tumors displayed rapid growth in both WT and MKR mice, and were more metastatic than CD24- cells. Interestingly, CD24-KD in CD24+ cells had no effect both in vitro and in vivo on the various parameters studied. Moreover, CD24(+) cells gave rise in vivo to the CD24(-) that comprised the bulk of the tumor. RNA-seq analysis revealed enrichment of genes and pathways of the extracellular matrix in the CD24(+) cells.ConclusionCD24(+) cells account for heterogeneity in mammary tumors. CD24 expression at early stages of the cancer process is an indication of a highly invasive tumor. However, CD24 is not a suitable therapeutic target; instead we suggest here new potential targets accounting for early differentiated cancer cells tumorigenic capacity.

Project description:Rationale: Cancer cells reprogram cellular metabolism to fulfill their needs for rapid growth and metastasis. However, the mechanism controlling this reprogramming is poorly understood. We searched for upregulated signaling in metastatic colorectal cancer and investigated the mechanism by which Glut3 promotes tumor metastasis. Methods: We compared RNA levels and glycolytic capacity in primary and metastatic colon cancer. The expression and association of Glut3 with clinical prognosis in colon cancer tissues was determined by immunohistochemistry. Glut3 gain-of-function and loss-of-function were established using colon cancer HCT116, HT29, and metastatic 116-LM cells, and tumor invasiveness and stemness properties were evaluated. Metabolomic profiles were analyzed by GC/MS and CE-TOF/MS. The metastatic burden in mice fed a high-fat sucrose diet was assessed by intravenous inoculation with Glut3 knockdown 116-LM cells. Results: Upregulation of glycolytic genes and glycolytic capacity was detected in metastatic colorectal cancer cells. Specifically, Glut3 overexpression was associated with metastasis and poor survival in colorectal cancer patients. Mechanistically, Glut3 promoted invasiveness and stemness in a Yes-associated protein (YAP)-dependent manner. Activation of YAP in turn transactivated Glut3 and regulated a group of glycolytic genes. Interestingly, the expression and phosphorylation of PKM2 were concomitantly upregulated in metastatic colorectal cancer, and it was found to interact with YAP and enhance the expression of Glut3. Importantly, a high-fat high-sucrose diet promoted tumor metastasis, whereas the inhibition of either Glut3 or YAP effectively reduced the metastatic burden. Conclusion: Activation of the Glut3-YAP signaling pathway acts as a master activator to reprogram cancer metabolism and thereby promotes metastasis. Our findings reveal the importance of metabolic reprogramming in supporting cancer metastasis as well as possible therapeutic targets.

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Metastatic colorectal cancer cells maintain the TGF? program and use TGFBI to fuel angiogenesis.

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Metastatic colorectal cancer cells maintain the TGFβ program and use TGFBI to fuel angiogenesis.

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