Abstract Cancer cachexia (CC) contributes significantly to cancer-associated mortality, yet the mechanisms leading to death in CC remain poorly defined. We investigated whether cardiac dysfunction is a driver of CC-associated mortality. Using continuous ECG telemetry and echocardiography during disease progression in the C26 model of CC, we comprehensively assessed the effect of cachexia on electrical and mechanical components of cardiac function. The development of cachexia was associated with significantly reduced mean stroke volume (baseline 30 μL vs. cachectic 13 μL, p = 0.001) and cardiac output (baseline 18 mL/min vs. cachectic 8 mL/min, p = 0.02), with significantly increased cardiac muscle atrophy at endpoint (baseline 145 mg vs. cachectic 110 mg, p 0.0001). Mortality was preceded by progressive conduction abnormalities, including first- and second-degree atrioventricular block, bradyarrhythmias, and atrial fibrillation. The onset of cachexia was associated with significantly reduced mean QTc duration (baseline 55 ms vs. cachectic 40 ms, p = 0.002), which correlated with marked hypercalcemia (baseline 8 mg/dL vs. cachectic 15 mg/dL, p 0.0001) and hypophosphatemia (baseline 6.5 mg/dL vs. cachectic 4.5 mg/dL, p = 0.0044). As an explanation for perturbed calcium homeostasis, we identified RNA and protein expression of parathyroid hormone-related protein (PTHrP) in C26 cancer cells. To investigate whether hypercalcemia was a driver of cachexia-associated cardiac dysfunction, we pharmacologically suppressed calcium levels with continuously infused zoledronic acid (ZA). ZA infusion significantly lowered mean plasma calcium (p = 0.05), delayed the onset of cachexia (p = 0.03), and partially preserved stroke volume and cardiac output. We hypothesized that if hypercalcemia is PTHrP-dependent, then isogenic PTHrP knockout in the C26 cell line would obviate cachexia. Mice bearing PTHrP-KO tumors remained non-cachectic with preserved electrical function (mean QTc: scramble 40 ms vs. KO 55 ms, p = 0.01) and preserved mechanical function (mean cardiac output: scramble 8 mL/min vs. KO 16 mL/min, p = 0.03) despite comparable tumor size to scramble controls. Taken together, these preclinical data demonstrate that tumor-derived PTHrP plays a major role in driving cachexia and associated cardiac dysfunction in the C26 model, and that cardiac dysfunction may be a final common pathway of mortality in CC. Our findings raise the possibility that PTHrP-driven cachexia may be a biologically distinct and therapeutically relevant subgroup of cancer cachexia. Citation Format: Tuba Mansoor Thakir, Sam Oscar Kleeman, Miriam Ferrer González, Tobias Janowitz. A tumor-derived PTHrP-calcium axis drives cardiac dysfunction to connect cancer cachexia with mortality abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5009.
Thakir et al. (Fri,) studied this question.