Biology subjects

Whelan, C. J.

Publications and source records attributed to Whelan, C. J..

6 recordsLinked to original sources

bioRxiv2026

Wasting is essential: cachexia is driven by a wound-healing adaptation

Background: Several explanations have been given for why cachexia occurs in the presence of severe acute wounds and chronic diseases. None of these explanations address the scope of clinical settings in which cachexia has been observed, nor do they account for the failure of nutritional support to reverse cachexia. We hypothesize that induced muscle wasting (IMW) is an adaptation to support wound healing, and when a wound does not heal, prolonged IMW leads to cachexia. Methods: To evaluate this hypothesis, we developed a mathematical model of IMW. In this model, we compared the time needed for wound healing when IMW was present and when it was inhibited. We also measured the relationship between the pathogen growth rate and final patient muscle mass for chronic diseases such as cancer and tuberculosis, demonstrating the onset of cachexia. Finally, we simulated the effects of nutritional support and contrasted the outcomes of when IMW was present and when it was inhibited. Results: Acute wound healing was ~2-6 times longer without IMW than with IMW. For chronic wounds, steady-state muscle mass strongly depended on the growth rate of the pathogenic agent. Inhibiting IMW was more effective at preventing acute muscle mass loss than nutritional support, and the benefit of nutritional support was enhanced by inhibiting IMW. Nutritional support also increased the speed of healing acute wounds when IMW was inhibited. For cancer with high growth rate, giving nutritional support alone had a negligible effect on steady-state muscle mass. But when IMW was inhibited, muscle mass loss was attenuated. With IMW inhibition, nutritional support with the normal diet was able to abrogate muscle mass loss entirely. Conclusions: Inhibiting IMW slows the healing of acute wounds, supporting our hypothesis that IMW is an adaptation to support rapid wound healing. Our experiments demonstrate that nutritional support is insufficient to prevent severe muscle mass loss while IMW continues. But when IMW is inhibited, nutritional support restores normal levels of muscle mass for both acute and chronic wounds, as well as increasing the rate of wound healing. Discovering and developing methods to inhibit IMW for clinical use will be essential to restore patient muscle mass, ease suffering, and reduce mortality.

systems biology↗

bioRxiv2024

Goliath clades and in vivo tracking of clonal dynamics show three phases of UV-induced skin carcinogenesis

While the genetic paradigm of cancer etiology has proven powerful, it remains incomplete as evidenced by the widening spectrum of non-cancer cell-autonomous "hallmarks" of cancer. Studies have demonstrated the commonplace presence of high oncogenic mutational burdens in homeostatically-stable epithelia. Hence, the presence of driver mutations alone does not result in cancer. Here, we reveal additional forces governing the eco-evolutionary dynamics of carcinogenesis. Using a UV-driven mouse model of cutaneous squamous cell carcinoma, we tested our central hypothesis that cancer initiation occurs in three phases: 1) tissue disruption and the emergence of unusually large "goliath" clades (ecological driver), 2) clonal selection within a subset of these goliaths as evidenced by the presence of areas of unusually high local densities of cells (termed "micro-lumps") with higher mutational burdens (evolutionary driver), and 3) emergence of macroscopic lesions. We tracked these tissue level ecological and evolutionary drivers of cancer initiation via in-vivo serial imaging and 3-D reconstruction of fluorescently labeled keratinocyte clades, yielding 25,085 clade measurements from 14 mice over 3 months, and 14,525 clades from 4 of these mice over 6 months. While median and mean clade sizes differed little between UV and non-UV exposure (cc. 65,000 {micro}m3), our ecological survey revealed the emergence of large goliath clades (> cc. 4.2x106 {micro}m3), almost exclusively within UV-exposed skin. Goliath clades emerged by month 2, increased dramatically in number by months 3-4, and plateaued between months 5-6. Goliath clades arose as serpentine structures, intercalating between adjacent keratinocytes. Unexpectedly, targeted DNA sequencing revealed mutations with very low variant allele frequencies within clades, but substantial differences among clades, suggesting that positive selection for these mutations is superfluous to the development of goliaths early in carcinogenesis. scRNAseq analysis of both bulk skin and sorted clades revealed epidermal de-differentiation and immune suppression as early events. By month 7, mutational burdens were significantly larger in goliath clades, particularly for those with micro-lumps. Finally, lesions began to emerge between months 6 and 7, only in UV-exposed skin. To confirm that goliath clades are orders of magnitude more likely to spawn lesions, we randomly selected 21 goliath clades at months 6-7, prior to the time of the emergence of detectable lesions, and followed them over time. Remarkably, 2 of these developed into macroscopic lesions. Our adaptation of the Drake equation estimated the probability of this to be <10-6. Taken together, our results support the presence of three phases of cancer initiation, the earliest of which presage the acquisition of driver mutations and also explains why cancers are relatively rare in relation to the degree of somatic mosaicism present in UV-exposed skin.

cancer biology↗

bioRxiv2023

L-DOS47 enhances response to immunotherapy in pancreatic cancer tumor

Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds CEACAM6, a cell surface protein highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO2, thereby raising local pH. To test the synergetic effect of neutralizing tumor acidity with immunotherapy, we developed a pancreatic orthotopic murine tumor model (KPC961) expressing human CEACAM6. Our results demonstrate that combining L DOS47 with anti-PD1 significantly increases the efficacy of anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks.

cancer biology↗

bioRxiv2020

Cycling hypoxia selects for constitutive HIF stabilization

Tumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-) in tumor cells are stabilized in response to low levels of oxygen and induce angiogenesis to re-supply oxygen. HIF- stabilization is typically facultative, induced by hypoxia and reduced by normoxia. In some cancers, however, HIF- stabilization becomes constitutive even under normoxia, a condition known as pseudohypoxia. Herein, we develop a mathematical model that predicts the effects of fluctuating levels of oxygen availability on stabilization of HIF- and its client proteins based on fitness. The model shows that facultative regulation of HIF- always promotes greater cell fitness than constitutive regulation. However, cell fitness is nearly identical regardless of HIF- regulation strategy when there are rapid periodic fluctuations in oxygenation. Furthermore, the model predicts that stochastic changes in oxygenation favor facultative HIF- regulation. We conclude that rapid and regular cycling of oxygenation levels selects for pseudohypoxia.

cancer biology↗

bioRxiv2017

The Use of Biogeographical Patterns to Assess Key Adaptations in Two Families of Birds

Adaptations can be thought of as evolutionary technologies which allow an organism to exploit environments. Among convergent taxa, adaptations may be largely equivalent with the taxa operating in a similar set of environmental conditions, divergent with the taxa operating in different sets of environmental conditions, or superior with one taxon operating within an extended range of environmental conditions than the other. With this framework in mind, we sought to characterize the adaptations of two convergent nectarivorous bird families, the New World hummingbirds (Trochilidae) and Old World sunbirds (Nectariniidae), by comparing their biogeography. Looking at their elevational and latitudinal gradients, hummingbirds not only extend into but also maintain species richness in more extreme environments. We suspect that hummingbirds have a superior key adaptation that sunbirds lack, namely a musculoskeletal architecture that allows for hovering. Through biogeographic comparisons, we have been able to assess and understand adaptations as evolutionary technologies among two convergent bird families, a process that should work for most taxa.

ecology↗

bioRxiv2017

The hummingbird and the hawk-moth:Species distribution, geographical partitioning, and macrocompetition across the United States

We introduce a new concept called macrocompetition - defined as the mutual suppression of diversity/species richness of competing clades - and investigate evidence for its existence. To this end, we analyzed the distribution of two convergent nectarivorous families, hawk-moths and hummingbirds, over the continental United States to determine whether there is geographic partitioning between the families and its potential causes. Using stepwise regression, we tested for latitudinal and longitudinal biases in the species richness of both taxa and the potential role of 10 environmental variables in their distribution pattern. Hawk-moth species richness increases with longitude (eastward-bias) while that of hummingbirds declines (westward-bias). Similar geographic patterns can be seen across Canada, Mexico and South America. Hawk-moth species richness is positively correlated with higher overall temperatures (especially summer minimums), atmospheric pressure, and summer precipitation; hummingbird species richness is negatively correlated with atmospheric pressure and positively correlated with winter daily maxima. The species richness patterns reflect each familys respective anatomical differences and support the concept of macrocompetition between the two taxa. Hawk-moth species richness was highest in states with low elevation, summer-time flowering, and warm summer nights; hummingbird species richness is highest in the southwest with higher elevation, greater cool season flowering and high daytime winter temperatures. Hawk-moths and hummingbirds as distinct evolutionary technologies exhibit niche overlap and geographical partitioning. These are two of three indicators suggested by Brown and Davidson for inter-taxonomic competition. We intend the patterns revealed here to inspire further exploration into competition and community structuring between hawk-moths and hummingbirds.

ecology↗