Autophagy and senescence in cancer-associated fibroblasts metabolically supports tumor growth and metastasis, via glycolysis and ketone production

Abstract

Senescent fibroblasts are known to promote tumor growth. However, the exact mechanism remains largely unknown. An important clue comes from recent studies linking autophagy with the onset of senescence. Thus, autophagy and senescence may be part of the same physiological process, known as the autophagy-senescence transition (AST). To test this hypothesis, human fibroblasts immortalized with telomerase (hTERT-BJ1) were stably transfected with autophagy genes (BNIP3, CTSB or ATG16L1). Their overexpression was sufficient to induce a constitutive autophagic phenotype, with features of mitophagy, mitochondrial dysfunction and a shift toward aerobic glycolysis, resulting in L-lactate and ketone body production. Autophagic fibroblasts also showed features of senescence, with increased p21(WAF1/CIP1), a CDK inhibitor, cellular hypertrophy and increased β-galactosidase activity. Thus, we genetically validated the existence of the autophagy-senescence transition. Importantly, autophagic-senescent fibroblasts promoted tumor growth and metastasis, when co-injected with human breast cancer cells, independently of angiogenesis. Autophagic-senescent fibroblasts stimulated mitochondrial metabolism in adjacent cancer cells, when the two cell types were co-cultured, as visualized by MitoTracker staining. In particular, autophagic ATG16L1 fibroblasts, which produced large amounts of ketone bodies (3-hydroxy-butyrate), had the strongest effects and promoted metastasis by up to 11-fold. Conversely, expression of ATG16L1 in epithelial cancer cells inhibited tumor growth, indicating that the effects of autophagy are compartment-specific. Thus, autophagic-senescent fibroblasts metabolically promote tumor growth and metastasis, by paracrine production of high-energy mitochondrial fuels. Our current studies provide genetic support for the importance of “two-compartment tumor metabolism” in driving tumor growth and metastasis via a simple energy transfer mechanism. Finally, β-galactosidase, a known lysosomal enzyme and biomarker of senescence, was localized to the tumor stroma in human breast cancer tissues, providing in vivo support for our hypothesis. Bioinformatic analysis of genome-wide transcriptional profiles from tumor stroma, isolated from human breast cancers, also validated the onset of an autophagy-senescence transition. Taken together, these studies establish a new functional link between host aging, autophagy, the tumor microenvironment and cancer metabolism.

The Role of Autophagia in Non-Small Cell Lung Cancer

“…Conclusively, the investigators stated that autophagia was effective in tumor growth independent of angiogenesis. 27 It was observed that CTSB expression was increased in tumor tissues compared to normal tissues in our cases in accordance with the literature.…”

Mitochondrial dysfunction in breast cancer cells prevents tumor growth

“…46 Similarly, genetic induction of ketone body production in cancer-associated fibroblasts (by expression of ATG16L1 or HMGCS2, or via silencing of the BRCA1 gene) promotes both tumor growth and/or metastasis. 27,32,47 Finally, genetic induction of mitochondrial biogenesis in cancer cells (by expression of PGC1-α/β; POLRMT; or MitoNEET) promotes tumorigenesis. 48 Thus, we have identified (1) stromal ketone production and (2) mitochondrial biogenesis in epithelial cancer cells as two key metabolic components which are energetically driving tumor cell growth and cancer cell metastasis.…”

“…These studies also validate the "two-compartment tumor metabolism" model of tumorigenesis. 21,[27][28][29][30][31][32][33][34] …”

Mitochondria “fuel” breast cancer metabolism: Fifteen markers of mitochondrial biogenesis label epithelial cancer cells, but are excluded from adjacent stromal cells

“…In direct support of this hypothesis, genetic induction of mitochondrial dysfunction in cancer-associated fibroblasts dramatically promotes both local tumor growth and distant cancer cell metastasis. [12][13][14][15][16][17][18][19][20][21][22][23][24] Conversely, genetic amplification of mitochondrial biogenesis in epithelial cancer cells also promotes tumor growth, independently of neo-angiogenesis. 23,[25][26][27][28] Consistent with these pre-clinical findings, we have identified a series of new stromal biomarkers and related gene signatures that are characteristic of this type of lethal cancer metabolism.…”