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Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in murine pancreatic cancer organoid-fibroblast co-cultures and tumors. Pancreatic cancer cells exhibited increased pyruvate carboxylation relative to fibroblasts, and this flux depended on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells was necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tissue.

Abstract Background While most cancer cells preferentially express the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2), PKM2 is dispensable for tumor development in several mouse cancer models. PKM2 is expressed in human pancreatic cancer, and there have been conflicting reports on the association of PKM2 expression and pancreatic cancer patient survival, but whether PKM2 is required for pancreatic cancer progression is unknown. To investigate the role of PKM2 in pancreatic cancer, we used a conditional allele to delete PKM2 in a mouse model of pancreatic ductal adenocarcinoma (PDAC). Results PDAC tumors were initiated in LSL-Kras G12D/+ ;Trp53 flox/flox ;Pdx-1-Cre (KP−/−C) mice harboring a conditional Pkm2 allele. Immunohistochemical analysis showed PKM2 expression in wild-type tumors and loss of PKM2 expression in tumors from Pkm2 conditional mice. PKM2 deletion had no effect on overall survival or tumor size. Loss of PKM2 resulted in pyruvate kinase M1 (PKM1) expression, but did not affect the number of proliferating cells. These findings are consistent with results in other cancer models. Conclusions PKM2 is not required for initiation or growth of PDAC tumors arising in the KP−/−C pancreatic cancer model. These findings suggest that, in this mouse PDAC model, PKM2 expression is not required for pancreatic tumor formation or progression.

Pancreatic ductal adenocarcinoma has a collagen-rich dense extracellular matrix that promotes malignancy of cancer cells. Here, the authors show that fibrillar collagen that is cancer-cell-derived, but not stroma-derived, selectively restrains tumor growth under control of their pC-proteinase, BMP1.

Abstract Background Cancer cells express the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2). PKM2 expression is not required for some cancers, and PKM2 loss can promote cancer progression; however, PKM2 has been reported to be essential in other tumor contexts, including a proposed non-metabolic role in β-catenin nuclear translocation. PKM2 is expressed in colon cancers where loss of the Apc tumor suppressor results in β-catenin nuclear translocation and aberrant activation of the canonical Wnt signaling pathway. Whether PKM2 is required in this colon cancer context has not been investigated. Results Colon tumorigenesis was induced in mice harboring conditional Apc and Pkm2 alleles, and tumor progression was monitored by serial colonoscopy. PKM2 deletion had no effect on overall survival, the number of mice that developed tumors, or the number of tumors that developed per animal. Immunohistochemical analysis demonstrated PKM2 expression in wild-type tumors and the expected loss of PKM2 expression in tumors from Pkm2 conditional mice. Loss of PKM2 resulted in pyruvate kinase M1 expression but had no effect on nuclear β-catenin staining. These findings are consistent with tumor growth and activated Wnt signaling despite PKM2 loss in this model. We also found a large fraction of human colon cancers had very low or undetectable levels of PKM2 expression. Conclusions PKM2 is not required for Apc-deficient colon cancer or for nuclear translocation of β-catenin in Apc-null tumor cells. These findings suggest that PKM2 expression is not required for colon tumor formation or progression.

Abstract Background Copy number gain of the D-3-phosphoglycerate dehydrogenase (PHGDH) gene, which encodes the first enzyme in serine biosynthesis, is found in some human cancers including a subset of melanomas. Methods In order to study the effect of increased PHGDH expression in tissues in vivo, we generated mice harboring a PHGDH tetO allele that allows tissue-specific, doxycycline-inducible PHGDH expression, and we analyzed the phenotype of mice with a ubiquitous increase in PHGDH expression. Results Tissues and cells derived from PHGDH tetO mice exhibit increased serine biosynthesis. Histological examination of skin tissue from PHGDH tetO mice reveals the presence of melanin granules in early anagen hair follicles, despite the fact that melanin synthesis is closely coupled to the hair follicle cycle and does not normally begin until later in the cycle. This phenotype occurs in the absence of any global change in hair follicle cycle timing. The aberrant presence of melanin early in the hair follicle cycle following PHGDH expression is also accompanied by increased melanocyte abundance in early anagen skin. Conclusions These data suggest increased PHGDH expression impacts normal melanocyte biology, but PHGDH expression alone is not sufficient to cause cancer.