Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer.

Here, we interrogated head and neck cancer (HNSCC) specimens (n = 12) to examine if different metabolic compartments (oxidative vs. glycolytic) co-exist in human tumors. A large panel of well-established biomarkers was employed to determine the metabolic state of proliferative cancer cells. Interestingly, cell proliferation in cancer cells, as marked by Ki-67 immunostaining, was strictly correlated with oxidative mitochondrial metabolism (OXPHOS) and the uptake of mitochondrial fuels, as detected via MCT1 expression (p < 0.001). More specifically, three metabolic tumor compartments were delineated: (1) proliferative and mitochondrial-rich cancer cells (Ki-67+/TOMM20+/COX+/MCT1+); (2) non-proliferative and mitochondrial-poor cancer cells (Ki-67-/TOMM20-/COX-/MCT1-); and (3) non-proliferative and mitochondrial-poor stromal cells (Ki-67-/TOMM20-/COX-/MCT1-). In addition, high oxidative stress (MCT4+) was very specific for cancer tissues. Thus, we next evaluated the prognostic value of MCT4 in a second independent patient cohort (n = 40). Most importantly, oxidative stress (MCT4+) in non-proliferating epithelial cancer cells predicted poor clinical outcome (tumor recurrence; p < 0.0001; log-rank test), and was functionally associated with FDG-PET avidity (p < 0.04). Similarly, oxidative stress (MCT4+) in tumor stromal cells was specifically associated with higher tumor stage (p < 0.03), and was a highly specific marker for cancer-associated fibroblasts (p < 0.001). We propose that oxidative stress is a key hallmark of tumor tissues that drives high-energy metabolism in adjacent proliferating mitochondrial-rich cancer cells, via the paracrine transfer of mitochondrial fuels (such as L-lactate and ketone bodies). New antioxidants and MCT4 inhibitors should be developed to metabolically target "three-compartment tumor metabolism" in head and neck cancers. It is remarkable that two "non-proliferating" populations of cells (Ki-67-/MCT4+) within the tumor can actually determine clinical outcome, likely by providing high-energy mitochondrial "fuels" for proliferative cancer cells to burn. Finally, we also show that in normal mucosal tissue, the basal epithelial "stem cell" layer is hyper-proliferative (Ki-67+), mitochondrial-rich (TOMM20+/COX+) and is metabolically programmed to use mitochondrial fuels (MCT1+), such as ketone bodies and L-lactate. Thus, oxidative mitochondrial metabolism (OXPHOS) is a common feature of both (1) normal stem cells and (2) proliferating cancer cells. As such, we should consider metabolically treating cancer patients with mitochondrial inhibitors (such as Metformin), and/or with a combination of MCT1 and MCT4 inhibitors, to target "metabolic symbiosis."

Dichogamy correlates with outcrossing rate and defines the selfing syndrome in the mixed-mating genus Collinsia.

BACKGROUND AND AIMS: How and why plants evolve to become selfing is a long-standing evolutionary puzzle. The transition from outcrossing to highly selfing is less well understood in self-compatible (SC) mixed-mating (MM) species where potentially subtle interactions between floral phenotypes and the environment are at play. We examined floral morphological and developmental traits across an entire SC MM genus, Collinsia, to determine which, if any, predict potential autonomous selfing ability when pollinators are absent (AS) and actual selfing rates in the wild, s(m), and to best define the selfing syndrome for this clade. METHODS: Using polymorphic microsatellite markers, we obtained 30 population-level estimates of s(m) across 19 Collinsia taxa. Species grand means for the timing of herkogamy (stigma-anther contact) and dichogamy (stigmatic receptivity, SR), AS, floral size, longevity and their genetic correlations were quantified for 22 taxa. KEY RESULTS: Species fell into discrete selfing and outcrossing groups based on floral traits. Loss of dichogamy defines Collinsia's selfing syndrome. Floral size, longevity and herkogamy also differ significantly between these groups. Most taxa have high AS rates (>80 %), but AS is uncorrelated with any measured trait. In contrast, s(m) is significantly correlated only with SR. High variance in s(m) was observed in the two groups. CONCLUSIONS: Collinsia species exhibit clear morphological and developmental traits diagnostic of 'selfing' or 'outcrossing' groups. However, many species in both the 'selfing' and the 'outcrossing' groups were MM, pointing to the critical influence of the pollination environment, the timing of AS and outcross pollen prepotency on s(m). Flower size is a poor predictor of Collinsia species' field selfing rates and this result may apply to many SC species. Assessment of the variation in the pollination environment, which can increase selfing rates in more 'outcrossing' species but can also decrease selfing rates in more 'selfing' species, is critical to understanding mating system evolution of SC MM taxa.