Maire, R. | bioRxiv Science

bioRxiv2025

Dual inhibition of lactate transporters MCT1 and MCT4 in pancreatic neuroendocrine tumors targets metabolic heterogeneity and functional redundancy

Our current understanding of the metabolic landscape of pancreatic neuroendocrine tumors (PanNETs) is very limited. Such knowledge could lead the development of novel therapeutic strategies for subgroups of PanNET patients based on the metabolic profile of their tumor. Here, we investigated the expression of lactate transporters MCT1 and MCT4 in two independent PanNET cohorts (n=93; n=70) and analyzed their association with tumor aggressiveness and therapeutic vulnerability in cell lines, spheroids and patient-derived tumoroids of PanNET. Immunohistochemistry revealed four expressor types: MCT1/4-negative, MCT1-positive, MCT4-positive, and MCT1/4-double positive with frequent regional co-expression. Both homogenous and heterogenous expression patterns were observed, indicating metabolic heterogeneity within the latter subset of PanNETs. MCT4 expression correlated with the hypoxia marker CA9, suggesting a hypoxic and acidic tumor microenvironment. Mechanistic studies revealed that MCT1 and MCT4 operate both as lactate efflux systems in PanNET cell lines, providing functional redundancy to their glycolytic roles. Inhibition of lactate efflux in normoxia and hypoxia using the dual MCT1/4 inhibitor syrosingopine significantly impaired lactate secretion, glycolysis, and proliferation across PanNET cell lines and 3D spheroid and patient-derived tumoroid models. In contrast, selective MCT1 or MCT4 inhibitors showed limited efficacy, underscoring the therapeutic need for co-targeting MCT1 and MCT4 due to functional redundancy and heterogenous expression. This work demonstrates MCT1 and MCT4 as metabolic markers and promising therapeutic targets of a subset of PanNETs with clinical features of aggressiveness.

cancer biology↗

bioRxiv2018

A multiscale stratigraphic investigation of the context of StW 573 Little Foot and Member 2, Sterkfontein Caves, South Africa

The Sterkfontein Caves has an 80 year history of yielding remarkable evidence of hominin evolution and is currently the worlds richest Australopithecus-beafing site. Included in Sterkfonteins hominin assemblage is StW 573 ( Little Foot). Discovered in the Member 2 deposit in the Silberberg Grotto, StW 573 represents the most complete Australopithecus skeleton yet found. Because of its importance to the fossil hominin record, the geological age of Little Foot has been the subject of significant debate. Two main hypotheses have been proposed regarding the formation and age of Member 2 and by association StW 573. The first, proposes that Member 2 formed relatively rapidly, starting to accumulate at around 2.8 million years ago and that the unit is isolated to the Silberberg Grotto - the underlying chambers and passages forming later. The second proposes that Member 2 formed slowly, its accumulation starting before 3.67 million years ago and that the deposit extends into the Milner Hall and close to the base of the cave system. Both assume a primary association between StW 573 and Member 2, although which sediments in the Silberberg Grotto are associated with Member 2 has also been questioned. Recently a third alternative hypothesis questioning the association of StW 573 to Member 2 sediments proposed a two-stage burial scenario in which sediments associated with StW 573 represent a secondary and mixed-age deposit reworked from a higher cave. The stratigraphic and sedimentological implications of these hypotheses are tested here through the application of a multiscale investigation of Member 2, with reference to the taphonomy of the Little Foot skeleton. The complete infilling sequence of Member 2 is described and depositional units are tracked across all exposures of the deposit in the Silberberg Grotto and into the Milner Hall. Facies development follows patterns characteristic of colluvially accumulated taluses with 30-40{degrees} angles of repose developing coarser distal facies. Sediments are generally stratified and conformably deposited in a sequence of silty sands eroded from well-developed lateritic soils on the landscape surface. Voids, clasts and bioclasts are organized consistently across and through Member 2 according to the underlying deposit geometry, indicating a gradual deposit accretion with no distinct collapse facies evident, no successive debris flow accumulation, and only localized intra-unit post- depositional modification. The stratigraphy and sedimentology of Member 2 supports a simple single-stage accumulation process through which Member 2 partially fills the Silberberg Grotto and extends into the deeper chambers and passages of the Sterkfontein Caves. Through this work we demonstrate at multiple scales the primary association between the sediments of Member 2 and the StW 573 Little Foot skeleton.

paleontology↗